1-alkyl-4-aminoquinaldinium salts



iinited grates Patent C 2,997,476 1-ALKYL-4-AMINOQUINALDINIUM SALTS Dennis Caldwell and Leonard Richard Rowe, London,

England, assignors to Allen 8: Hanburys Limited, London, England, a British company No Drawing. Filed June 2, 1959, Ser. No. 817,497 Claims priority, application Great Britain June 19, 1958 7 Claims. (Cl. 260286) The invention relates to 1-alkyl-4-arninoquinaldinium salts.

The novel compounds of the present invention are 1- alkyl-4-aminoquinaldinium salts of the general formula:

-( 2)DCHs where n is an integer of from 6 to 17 inclusive and X is an anion such as a halide or an acetate.

The compounds of the present invention are useful anti-microbial agents.

The preferred compounds are those in which n is 9, 11, 13 and 15 and the most preferred compound is l-dodecyl- 4-aminoquina1dinium acetate.

The present invention also includes a process for the manufacture of the novel compounds of the present invention wherein one molecular proportion of 4-aminoquinaldine and more than one molecular proportion of an alkyl halide containing from 7 to 18 carbon atoms inclusive are heated together alone or in the presence of an organic solvent for at least 25 hours, for example, for 25 to 100 hours.

The product may be isolated by cooling the reaction mixture and filtering off the solid; it may then be purified by recrystallisation.

Examples of organic solvents which may be used are methyl ethyl ketone, methyl isobutyl ketone and methyl isobutyl carbinol.

Preferably the heating is conducted under reflux.

The resulting quaternary halides may be converted by conventional methods, eg double decomposition, into other quaternary salts such as the acetate, chloride, bicarbonate, lactate, succinate, maleate and tartrate.

The following examples illustrate the invention:

EXAMPLE 1 Preparation of 1-heptyl-4-aminoquinaldinium iodide 32 g. of 4-aminoquinaldine, 55 g. of heptyl iodide and 400 ml. of methyl ethyl ketone were refluxed together for 70 hours. The mixture was allowed to cool, the solid was filtered off, washed with methyl ethyl ketone and recrystallised from ethyl alcohol. The product Was a White powder, melting point 225 C.

EXAMPLE 2 Preparation of 1-decyl-4-amin0quinaldinium iodide 32 g. of 4-aminoquinaldine, 61 g. of decyl iodide and 400 ml. of methyl isobutyl ketone were refluxed together for 5 0 hours. The mixture was allowed to cool, the solid filtered, washed with methyl isobutyl ketone and recrystallised from isopropyl alcohol. The product was a pink solid, melting point 197 C.

Preparation of 1-decyl-4-aminoquinaldinium chloride 6.5 g. of 1-decyl-4-aminoquinaldinium iodide, 2.4 g. of silver chloride and 100 ml. of isopropyl alcohol were refluxed together for 4 hours. The reaction mixture was 2397,4276 Patented Aug. 22, 1961 EXAMPLE 3 Preparation of 1-dodecyl-4-anzinoquinaldinium iodide 19 g. of 4-amin0quinaldine, 50 g. of dodecyl iodide and 300 ml. of methyl ethyl ketone were refluxed together for hours. The mixture was allowed to cool, the solid filtered off, washed with methyl ethyl ketone and recrystallised from a mixture of isopropyl alcohol and water. The product was a white powder, melting point 177l78 C.

EXAMPLE 4 Preparation of 1-tetradecyl-4-amin0quinaldinium iodide l g. of 4-arr1inoquinaldine and 10 g. of tetradecyl iodide were heated together at 175 C. for 25 hours. The reaction mixture was cooled, 50 ml. of isopropyl acetate added and refluxed for 30 minutes. The reaction mixture was filtered hot and the solid so obtained was recrystallised from acetone. The product Was a pink solid, melting point 176-177 C.

Preparation of 1-tetradecyl-4-aminoquinaldinium acetate 5.0 g. of 1-tetradecyl-4-aminoquinaldiniurn iodide was dissolved in 20 ml. of methanol and 1.75 g. of silver acetate added. The mixture was stirred in the dark at room temperature for. 14 hours, filtered, and the methanol evaporated. The residue Was recrystallised from acetone. The product was a white solid, melting point 152-153 C.

EXAMPLE 5 Preparation of 1-hexadecyl-4-aminoquinaldinium iodide 17 g. of 4-aminoquinaldine, 50 g. of hexadecyl iodide and 250 ml. of methyl ethyl ketone were refluxed together for 80 hours. The mixture was allowed to cool, the solid filtered, washed with methyl ethyl ketone and recrystallised from a mixture of isopropyl alcohol and water. The product was a pink solid, melting point 157-158" C.

EXAMPLE 6 Preparation of 1-octadecyl-4-aminoquinaldiniam iodide 17.1 g. of 4-aminoquinaldine, 50 g. of octadecyl iodide and 300 ml. of methyl ethyl ketone were refluxed together for hours. The mixture was allowed to cool, the solid filtered, washed with methyl ethyl ketone and re crystallised from a mixture of acetone and isopropyl alcohol. The product was a pink solid, melting point C.

EXAMPLE 7 Preparation 0 1-undecyl-4-aminoquinaldinium iodide 22.5 g. of 4-aminoquinaldine, 50 g. of undecyl iodide and 300 ml. of methyl ethyl ketone were refluxed together for 90 hours. The mixture was allowed to cool, the solid was filtered off, washed with methyl ethyl ketone and recrystallised from a mixture of isopropyl alcohol and water. The product was a pink powder, melting point EXAMPLE 8 Preparation of 1-dodecyl-4-aminoquinaldinium lactate 9.1 g. of 1-dodecyl-4-aminoquinaldinium iodide was dissolved in 50 ml. of methanol and 3.9 g. of silver lactate added. The mixture was stirred in the dark at room temperature for 14 hours, filtered and the methanol evaporated. The residue was recrystallised from isopropyl acetate. The product was a white solid, melting point 15 1-152 C.

EXAMPLE 9 Preparation f1-d0decyl-4-aminoquinaldinium acetate 18.16 g. of 1-dodecyl-4-aminoquinaldinium iodide was dissolved in 70 ml. of methanol and 6.68 g. of silver acetate added. The mixture was stir-red in the dark at room temperature for 4 hours, filtered and the methanol evaporated. The residue was recrystallised from acetone. The product was a white solid, melting point 170-171 C.

EXAMPLE Preparation of 1-dodecyl-4-aminoquinaldinium succinate 4.5 g. of l-dodecyl-4-aminoquinaldinium iodide was dissolved in 20 ml. of methanol and 2.25 g. of silver succinate added. The mixture was stirred in the dark at room temperature for 16 hours, filtered and the methanol evaporated. The residue was [recrystallised from ethyl alcohol. The product was a white solid, melting point 238-240" C.

EXAMPLE 11 Preparation of I-dodecyl-4-amin0qninaldinium bicarbonate 10 g. of l-dodecyl-4-aminoquina1dinium acetate was dissolved in 100 ml. of distilled water and the solution was heated to 80 C. A solution of 3.9 g. of potassium bicarbonate in 39 ml. of distilled water was added, the precipitate was filtered off and recrystallised from distilled water. The product was a pink solid of melting point 135-136 C.

EXAMPLE 12 Preparation of 1-d0decyl-4-aminoquinaldin ium maleate 1 g. of 1-dodecyl-4-aminoquinaldinium bicarbonate was dissolved in 20 ml. of methanol, heated to 60 C. and 0.3 g. of maleic acid added. The solvent was removed in vacuo. The residual oil crystallised on trituration with isopropyl acetate to give a white solid of melting point 9798 C.

EXAMPLE 13 Preparation 07"1-dodecyl-4-amin0qainaldinium tartrate 1.9 g. of 1-dodecyl-4-aminoquinaldinium bicarbonate was dissolved in 30 ml. of methanol and 0.75 g. of tartaric acid added. The methanol was evaporated and the residual oil was recrystallised from methyl ethyl ketone to give a white crystalline solid of melting point 168-169 C.

Results of investigations into the bacteriostatic activity of the compounds of the present invention are given in Table I in which the results are expressed as the minimal inhibitory concentration (M.I.C.) in ng. of the base per ml.

TABLE I.BACTERIOSTATIC ACTIVITIES IN PEPTONE WATER WITH 0.5% DEXTROSE AND 0.5% SODIUM CHLO- IDE OF SOME 1-ALKYL-4-AMINOQUINALDINIUM ACE- ATES [Readings taken after 5 days incubation at 37 0.]

Bacteriostatic activity (M.I.O.) ig/ml.

Micro-organism Compound in which n in the general Formula I is- S. aureus CN.491 1. 9 0.31 0.14 E. 01 12. 50 8.80 100 100 0. 34 0.17 0.16 0.13 0. 78 0. 39 1.40 0.35 2. 21 50 50 0.35 1. 4

The bactericidal activity of some compounds of the present invention has also been investigated and the results are illustrated by Tables 11 and III.

TABLE II.BACTERICIDAL ACTIVITY OF SOME l-ALKYL- 4-AMINOQUINALDINIUM ACETATES S. aureus ONAQI--. E. coli Proteus 3p".-. P8. pyocyanea S. saprophytz'cus. Sarcina lutea... S. viridcms TABLE IV.ACTIVITY IN VITRO OF SOME l-ALKYL- i- AMINOQUINALDINIUM ACETATES AGAINST VARIOUS MICROBIAL SPECIES Fungistatic activity expressed as minimal inhibitory concentration in pg. per ml.

Sample T. Actino- Derma- C'.albiintermyces tophilus M.

was digitale bovis dermacams tonomus 1-Heptyl-4-amino-quinaldinium acetate 40.00 20.00 1-Decyl-4-ammo-quinaldinium acetate 1. 25 5.0 l-Dodecyl-4-amino-quinaldinium acetate 1.25 5.0 50 0.55 6. 25 1-Tetradecyl-4-amino-quinaldiuium acetate 2.50 10.00 l-Hexadecyli-amino-quin aldinium acetate 10.00 28. 20 Griseoiulvin 100 0. 78

The efiect of the compounds of the present invention upon normal skin micro-organisms in human volunteers is illustrated in Table V. In these experiments areas of the skin on the forearms of the volunteers were swabbed and the swabs incubated in nutrient glucose broth, into which an agent for inactivating the compounds remaining on the swab had been incorporated.

Selected skin areas were then treated with the test solutions and allowed to dry. The areas were again swabbed and the swabs incubated at 37 C. for 48 hours.

TABLE V Effect of some l-alkyl-4-aminoquinaldmium salts on normal skin microorganisms of humans No. of positive swab cultures Solution used after incubation at 37 C. for 48 hours 6/6 6/6 1% 1-dodecyl-4-aminoquinaldinium acetate in 70% alcohol 4/6 1% cetyl trimethyl ammonium bromide in 70% alcohol 6/6 Controls 7/7 5% aqueous solution of l-dodecyl-4-aminoquinaldmium acetate 2/7 5% ditto in 70% alcohol 1/7 1% l-dodecyl-tt-aminoquinaldinium iodide in 70% alcohol A 1/7 The efiect of the compounds of the present invention against pathogenic organisms present on human skin has been investigated. In the experiments the results of which are recorded in Tables VI and VII, two areas were defined on the forearms of human volunteers. Both areas Were swabbed with a suspension of either Proteus sp. of Ps. pyocyanea and allowed to dry, one area was then treated with a test solution which was allowed to dry, and the second area was left untreated. Each area was then swabbed with a swab soaked in broth and the swabs were incubated in nutrient broth for 4 hours at 37 C.

Number of positive swab cultures after incubation at 37 0. for 48 hours.

Proteus up. Pa. pyocyanea 1% aqueous solution of 1 eeyl--aminoquinaldiuium acetate 6 What We claim is: I l. 1-alkyl-4-aminoquinaldinium salts of the formula:

CH3 N/ (CH2)nCH3 X.-

where rz is an integer of from 6 to 17 inclusive and X is a non-toxic anion.

2. 1-alkyl-4-aminoquinaldinium salts of the formula:

References Cited in the file of this patent UNITED STATES PATENTS Austin et al. May 7, 1957 OTHER REFERENCES Ochiai: Chem. Abstracts, p. 6637, vol. (1951). 

1. 1-ALKYL-4-AMINOQUINALDINIUM SALTS OF THE FORMULA: 